Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss and/or atrophy of neurons in discrete regions of the brain, accompanied by extracellular deposits of β-amyloid and the intracellular accumulation of neurofibrillary tangles. It is a uniquely human disease, affecting over 13 million people worldwide. It is also a uniquely tragic disease. Many individuals who have lived normal, productive lives are slowly stricken with AD as they grow older, and the disease gradually robs them of their memory and other mental faculties. Eventually, they even cease to recognize family and loved ones, and they often require continuous care until their eventual death.
Alzheimer's disease is incurable and untreatable, except symptomatically. Persons suffering from Alzheimer's disease may have one of two forms of this disease: “familial” AD or “sporadic” AD.
Familial Alzheimer's disease accounts for only about 5 to 10% of all Alzheimer's cases and has an unusually early-onset, generally before the age of fifty. Familial AD is inherited and follows conventional patterns of mendelian inheritance. This form of AD has been linked to nuclear chromosomal abnormalities.
In contrast, the second form of Alzheimer's disease, sporadic AD, is a late-onset disease which is neither inherited nor caused by nuclear chromosomal abnormalities. This late onset form of the disease is the more common type of Alzheimer's disease and is believed to account for approximately 90 to 95% of all Alzheimer's cases.
It has been recognized that some degenerative diseases such as Leber's hereditary optic neuropathy, myoclonus, epilepsy, lactic acidosis and stroke. (MELAS), and myoclonic epilepsy ragged red fiber syndrome, are transmitted through mitochondrial DNA mutations. Mitochondrial DNA mutations have also been implicated in explaining the apparently “sporadic” (nonmendelian) occurrence of some degenerative neurologic disorders, such as Parkinson's and Alzheimer's disease. Proteins encoded by the mitochondrial genome are components of the electron transport chain, and deficits in electron transport function have been reported in Parkinson's and Alzheimer's disease. In particular, it has been reported that defects in cytochrome c oxidase, an important terminal component of the electron transport chain located in the mitochondria of eukaryotic cells, may be involved in Alzheimer's disease.
One report suggesting a relation between AD and cytochrome c oxidase is Parker et al., Neurology 40: 13021303 (1990), which finds that patients with Alzheimer's disease have reduced cytochrome c oxidase activity. It has also been shown by Bennett et al., J. Geriatic Psychiatry and Neurology 5:93-101 (1992), that when sodium azide, a specific inhibitor of cytochrome c oxidase (COX) was infused into rats, the rats suffered impaired memory and learning (a form of dementia). The rats mimicked the effect of Alzheimer's disease in humans. In addition, the sodium azide-tested rats failed to display long term potentiation, demonstrating loss of neuronal plasticity. It has been hypothesized that the reduced cytochrome c oxidase activity leads to increased intracellular levels of oxygen free radicals, and that the cumulative effects of free radical-mediated lipid oxidation ultimately cause the degenerative neurological changes that are characteristic of AD. Wallace, D. C., Science, 256:628-632 (1992).
Despite these findings, prior to the present invention, the exact mechanism producing the electron transport dysfunctions was not known for Alzheimer's disease, nor had a genetic or structural basis for these dysfunctions been identified. Without knowing what causes these electron transport dysfunctions and in particular the genetic or structural basis, it is difficult to diagnose or treat Alzheimer's disease, especially the predominant form, sporadic AD.
To date, the diagnosis of probable Alzheimer's disease is only by clinical observation and is a diagnosis of exclusion. Unfortunately, definitive diagnosis can be accomplished only by pathological examination at autopsy. While attempts have been made to diagnose Alzheimer's disease by identifying differences in certain biological markers, including protease nexin II and apolipoprotein E alleles, this approach has not been successful. Incomplete penetrance in AD patients or crossover into normal or other disease populations makes identification of biological markers an unreliable method of diagnosis. Clearly, a reliable diagnosis of Alzheimer's at its earliest stages is critical for efficient and effective intercession and treatment of this debilitating disease. Thus, there exists a definite need for an effective diagnostic of Alzheimer's disease, and especially for the more prevalent form, sporadic AD. There also exists a need for a non-invasive diagnostic that is reliable at or before the earliest manifestations of AD symptoms.
Not only does the Alzheimer's field currently lack a reliable, early means of detection, there is at present no effective therapy for AD, other than certain palliative treatments. Current therapies in clinical evaluation are designed to treat the symptoms of the disease and not impact the underlying pathology of AD. These therapies include Cognex, E2020, and other similar agents known in the field. However, since the primary etiologic events in AD are not yet known in the art, rational therapies have not been designed. As a result, there exists a need for effective therapies, particularly those that address the primary cause of AD.
The present invention satisfies these needs for a useful diagnostic and effective treatment of Alzheimer's disease and provides related advantages as well.